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Ultra-high-resolution postmortem MRI of cortical lesions in a nonhuman primate model of multiple sclerosis1Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States, 2Cerebral Microcirculation Section, Laboratory of Functional and Molecular Imaging, National Institutes of Health, Bethesda, MD, United States, 3Viral Immunology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
Synopsis
Experimental autoimmune encephalomyelitis (EAE) in the common marmoset (Callithrix jacchus) shares important pathological and radiological similarities with MS. However, cortical pathology in this model has not been investigated by MRI. The purpose of this study is to examine, for the first time, whether cortical lesions can be visualized by MRI in this model. Similar to MS patients, we report the MRI detection of MS-like cortical lesions in postmortem EAE marmoset. These findings further reinforce the proximity between this animal model and the human disease.
Introduction:
Cortical pathology is thought to be a major driver of disability and progression in multiple sclerosis1. However, detecting cortical lesions in MS patients with MRI remains challenging2. Insufficient spatial resolution (even at 1mm isotropic), low levels of inflammation, and partial volume effect with surrounding cerebrospinal fluid all hamper in vivo detection of cortical lesions. As such, little is known about the dynamics of cortical lesion formation and repair. To address this issue, animal models are attractive due to their flexibility for developing novel imaging strategies, which can be validated with gold-standard histopathological techniques. Among these models, experimental autoimmune encephalomyelitis (EAE) in the common marmoset (Callithrix jacchus) shares important pathological and radiological similarities with MS with respect to white matter pathology3-6. Cortical pathology is also known to affect marmosets with EAE but has not been investigated in depth by MRI7. The purpose of this study is to investigate, for the first time, whether cortical lesions can be visualized by MRI in a non-human primate EAE model.Methods:
Animals: Half-brains from 9 marmosets (3 right and 6 left hemispheres; 8 females and 1 male; 7 EAE and 2 healthy controls) were scanned at 7-tesla. All brains were perfused with 4% paraformaldehyde during necropsy, post-fixed in 10% neutral buffered formalin, and scanned with and without gadolinium-based preparation. This preparation consisted of soaking the half-brains in 50 ml of deionized water and 0.2 ml of gadolinium contrast agent (gadobutrol) for 10 days in order to shorten the T1 relaxation time of the tissues and to increase the signal-to-noise ratio (SNR) and contrast between white and gray matter (Fig 1). MRI: Postmortem imaging was performed in a 7 T/30 cm scanner (Bruker Biospin, Ettlingen, Germany). Tissues were maintained with a 3D printed holder8 placed inside a plastic tube filled with Fomblin (Solvay, Brussels, Belgium) and inserted into a 30-mm inner diameter quadrature coil (Milipede coil, Varian Inc, Palo Alto, CA, US). 3D T2* weighted acquisitions were performed overnight to obtain high SNR images (TE = 24 or 34 ms; TR = 62 ms; FA = 75°; voxel size = 50 μm isotropic; NSA = 5 or 6; AT = 2 hours 30 min per acquisition) (Fig 2). Histopathology: Brain tissues were paraffin-embedded and sectioned in 5-μm-thick slices. To detect demyelination in the cortex, myelin proteolipid protein (PLP) immunohistochemistry was performed. The staining was visualized by di-aminobenzidine (DAB) and digitally scanned with a Zeiss microscope.Results:
4 out of the 7 EAE half-brains showed cortical lesions on 3D T2*
weighted images when gadolinium preparation was used (Fig 3). The distribution of cortical lesions was heterogenous in
terms of lesion location (temporal, parietal, and frontal cortices, pre- and
post-central areas, entorhinal cortex) (Fig
3) and lesion type (leukocortical, intracortical, and subpial) (Fig 4 A). None of these cortical lesions
were identified without gadolinium preparation. Additionally, no cortical lesions
were identified in the two healthy brains. PLP staining confirmed the presence
of the cortical lesions identified by MRI (Fig
4 BC). Note that a central vein could be observed in all of the leukocortical
and intracortical lesions.Discussion/Conclusion:
We report the MRI detection of MS-like cortical lesions in the marmoset EAE model. Similar to MS patients9,10, marmosets with EAE present a heterogenous distribution of cortical lesions in various brain areas, as well as all major subtypes of cortical lesions. These findings further reinforce the proximity between this animal model and the human disease. Our results open a pathway toward future MRI sequence development for imaging cortical lesions in vivo.Acknowledgements
No acknowledgement found.References
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